The Science of Rheumatoid Arthritis

Question 1

Describe the structure of the synovium

Answer 1

2 Layers:
- Intimal layer (in contact with fluid): made up of macrophages and fibroblasts

Subintimal Layer: contains blood vessels, macrophages and fibroblasts

Question 2

What are the functions of the synovium?

Answer 2

• Maintenance of intact tissue surface
• Lubrication of cartilage (h. acid & lubricin)
• control of synovial fluid volume
• Nutrition of chondrocytes

Question 3

What happens to the synovium in rheumatoid arthritis?

Answer 3

There is synovitis, inflammation of the synovium

Question 4

What is rheumatoid arthritis defined as? What areas are most affected by RA?

Answer 4

The chronic, symmetric, polyarticular inflammation of joints. it is an immune mediated disease

Mainly affects the joints of the hands and feet

Question 5

What is the pannus? What does it do?

Answer 5

The pannus is the inflammatory tissue of the synovium, characterized by inflammatory cells, synoviocyte proliferation and neoangiogenesis

The pannus causes destruction of bone and articular cartilage in RA bones

Question 6

What are the targets of the autoantibodies that contribute to the development of rheumatoid arthiritis?

Answer 6

• Joint antigens such as type II collagen

- Systemic antigens such as glucose phosphate isomerase

Question 7

What are the two types of RA patients depending on autoantibody production?

Answer 7

Seropositive (RF / ACPA is detected)

Seronegative

Question 8

What are the two common autoantibodies produced in rheumatoid arthritis? Which carries a less favourable prognosis?

Answer 8

• Rheumatoid factor

- Anti-citrullinated protein antibody (ACPA)

Question 9

What causes rheumatoid arthritis?

Answer 9

Disease is at its roots genetic, but in genetically susceptible patients environmental factors may play a role:

• Smoking
• Infection (EBV / CMV / E. Coli / Mycoplasma)

Question 10

What is citrullination? How is citrullination implicated in RA?

Answer 10

The conversion of the AA arginine into citrulline in a protein

Abnormal citrullination results in the development of altered antigens that are no longer recognized as self antigens, triggering an autoimmune response

Question 11

Describe the pathophysiology of the autoimmune response in rheumatoid arthritis

Answer 11

Environmental and genetic factors interact to cause altered post-transcriptional regulation that leads to inappropriate self protein citrullination which facilitates the loss of tolerance and development of autoimmunity

Question 12

What cellular changes characterize the synovitis in rheumatoid arthritis?

Answer 12

• Intimal lining hyperplasia
• Infiltration of T, B and C cells, as well as macrophages
• Excessive proliferation of fibroblasts
• Inappropriate production of cytokines and proteases
• Neoangiogenesis
• Antibody production

Question 13

What is the role of T cells in RA?

Answer 13

• Production of cytokines
• Activation of B cells
• Activation of macrophages

Question 14

What is the role of B cells in RA?

Answer 14

• Production of autoantibodies
• Autoantigen presentation
• Production of cytokines

Question 15

What is the role of the cytokines produced in RA?

Answer 15

• Induce expression of endothelial cell adhesion molecules (recruit circulating cells to synovium)
• Activate synovial fibroblasts, chondrocytes and osteoclasts
• Promote angiogenesis
• Suppress T-regs
• Activate leukocytes & autoantibody production

Question 16

What triggers the neoangiogenesis seen in RA?

Answer 16

• Hypoxic conditions and angiogenic factors such as IL-8 and VEGF

Question 17

What is responsible for the cartilage and bone destruction seen in RA?

Answer 17

• Fibroblasts responsible for cartilage damage via metalloproteinases and aggrecanases
• Increase in osteoclast number due to production of RANKL by the synovium causes bone destruction

Question 18

What are the key cytokines involved in the inflammatory response characteristic of rheumatoid arthritis?

Answer 18

TNF-alpha
IL-1
IL-6
RANK-Ligand 
IL-17

Question 19

Describe the mechanism behind the increase in osteoclast number characteristic of RA

Answer 19

There is increased production of IL-1, TNF and IL-17 by the T cells and fibroblasts

This causes an increase in RANKL levels

Increase RANKL levels causes increased differentiation of myeloid cells into osteoclasts

Question 20

What are some of the systemic consequences of the inflammation seen in rheumatoid arthritis?

Answer 20

• Vasculitis, rheumatoid nodules, scleritis, amyloidosis
• CVS disease (altered lipid metabolism etc.)
• Fatigue and reduced cognitive function
• Hepatic disease (elevated acute phase response / anaemia)
• Interstitial lung disease / fibrosis
• Sarcopenia (loss of muscle mass)
• Osteoporosis
• Secondary Sjogren’s syndrom (dry eyes & mouth)